A study on p16, pRb, cdk4 and cyclinD1 expression in non-small cell lung cancers
Introduction
Non-small cell lung cancer is a malignant tumor which seriously threatens human health. Modern tumor molecular biological studies 1, 2, 3prove that the mechanisms for controlling tumor growth might involve direct regulation of the cell cycle which is regulated by a series of catalytic protein kinase complexes [4]consisting of cyclins (regulatory subunit), cyclin-dependent kinases (cdks) (catalytic subunit) and some others. The activation of corresponding substrates triggers of the corresponding cell phases. cdk4 and cyclinD1 are strongly implicated in the control of G1 progression and the phosphorylation of the retinoblastoma protein (pRb) 5, 6. p16 was found to be altered in many human malignant tumor cell lines and primary tumors 5, 7and p16 protein could specifically interact with cyclinD1 to inhibit the activity of cyclin-dependent kinase4 (cdk4); the latter could catalyze the pRb.
One hundred four cases of resected non-small cell lung cancer (NSCLC) were collected. The expression of p16, pRb, cyclinD1 and cdk4 in NSCLC was investigated by immunohistochemistry (LSAB method). The relationship of expression of p16, pRb, cdk4 and cyclinD1 was studied.
Section snippets
Materials and methods
One hundred four cases of resected NSCLC were collected from our hospital; these included squamous cell carcinomas (n=58), adenocarcinomas (n=41) and large cell carcinomas (n=5). All of the samples were surgically resected and had not previously received either chemotherapy or radiotherapy.
Rabbit polyclonal p16, pRb and cdk4 antibodies were purchased from Santa Cruz Biotechnology and mouse monoclonal cyclinD1 antibody was from NOVO. The DAKO avidin–biotin complex kit was used for detection
Immunostaining with anti-p16 antibody
The nuclei of the positive cells were stained a brownish yellow color (Fig. 1Fig. 2). The p16 expression of tumors was significantly lower than that of normal mucosal epithelium (P<0.001), which implied that the p16 gene was downregulated in tumor cells. The positive expression rate in squamous cell carcinoma and adenocarcinoma was 67.2 and 46%, respectively (Table 1). Additionally, the positive rate of squamous cell tumor was significantly higher than that of adenocarcinoma (χ2=4.32, P<0.05).
Discussion
The absence of p16 expression is a common molecular abnormality in NSCLC 2, 9, 10. In this study, about 40% of lung cancers did not express p16, 52% of cancers partly expressed p16 and 90% of normal mucosal epithelium expressed p16 (P<0.01), which shows that p16 is downregulated in NSCLC and implies that p16 is an important factor in the development of lung cancers. One of the mechanisms of p16 expression was hyperthylation of a G:C rich region within exon 1 of the p16 gene [11]. The expression
References (17)
- et al.
Genetic etiology of lung cancer
Oncol. Huntingt
(1992) - et al.
Rb and p16INK4a in resected non-small cell lung tumors
Cancer Res.
(1996) - et al.
P53 mutations in human cancers
Science
(1991) Ordering S phase and M phase in the cell cycle
Cell
(1994)- et al.
A cell cycle regulator potentially involved in genesis of many tumor types
Science
(1994) - et al.
Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition
Nature
(1995) - et al.
Mutations and altered expression of p16ink4 in human cancer
Proc. Natl. Acad. Sci. USA
(1994) - et al.
Immunohistochemical detection of the cyclin-dependent kinase inhibitor 2/multiple tumor suppressor gene 1 product p16 in archival human solid tumors: correlation with retinoblastoma protein expression
Cancer Res.
(1995)
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